Hepcidin – hormonal link in the interplay of systemic iron and glucose

Introduction: Diseases of glucose metabolism such as diabetes mellitus are mostly associated with elevated body iron status, and diseases of iron overload are often accompanied by type 2 diabetes. The molecular mechanism of such intriguing mutual relationships between iron and glucose metabolisms still remained enigmatic. Here we provide evidence that body iron and glucose profile is connected by the hormonal peptide hepcidin, originally identified as an antimicrobial defensin-like peptide in the liver.

Methods: Peptide-specific antibodies were raised to localize hepcidin in human and rat pancreatic islets using immunohistochemistry and electron microscopy. Regulation of hepcidin expression was analyzed in RINm5F, rat insulinoma cells, using quantitative RT-PCR. Secretion of hepcidin into the plasma after glucose application was measured by ELISA.

Results: Hepcidin is specifically expressed in pancreatic ß-cells and co-localized with insulin in secretory granules. Stimulation of ß-cells with glucose induces co-secretion of insulin and hepcidin with parallelly increasing serum concentrations. Beyond the well-known effect of insulin on glucose metabolism increases of hepcidin serum concentrations lead to a decrease of body iron stores as evidenced stressing the ambiguous glucose/iron-regulatory function of the pancreatic ß-cell. The expression of hepcidin in ß-cells at the transcriptional and translational levels is likewise under control of both iron and glucose.

Conclusions: The present data clearly show the impact of pancreatic hepcidin in linking glucose and iron metabolisms and may provide insight into the phenomenology of glucose/iron metabolic disorders such as in hereditary hemochromatosis, an iron overload disease with abnormal glucose homeostasis and decreased insulin secretion.